Intravenous drug use (IVDU) and HIV-1 infections are two linked global health crises since needle sharing is a well-recognized mode of HIV-1 transmission. Drugs of abuse accelerate the incidence and progression of HIV- 1-associated neurological disorders (HAND). Drug-abusing HIV-1 positive individuals exhibit more severe cognitive impairment compared with the non-drug-abusing HIV positive counterparts. Cocaine, often abused by HIV-infected patients, has been suggested to worsen HIV-associated CNS disease. Although antiretroviral therapy (ART) has diminished the incidence of HIV-1-associated dementia (HAD), milder forms of neurological disease do persist. Increased survival rates resulting from ART therapy usage have led to an increase in the prevalence of HAND. Despite the recognized impact of the abuse of cocaine on the clinical course of HIV-1- associated brain pathology; mechanisms underlying the ability of cocaine to enhance the pathological effects of HIV-1 in the brain remain elusive. It is well-recognized that despite near complete suppression of viremia in the face of ART, early viral proteins such as HIV Tat are found lurking in tissue sites, thereby contributing to residual chronic neuroinflammation/glial activation observed in HAND. Recent studies indicate ER stress as a protective response by the cell against external injury/insult. Our preliminary studies the indicate role of ER stress in HIV Tat-mediated upregulation of GFAP (astrogliosis) in primary rat astrocytes. Whether cocaine cooperates with HIV Tat to synergistically induce astrogliosis via the ER stress pathway, remains unknown. We hypothesize that HIV Tat & cocaine via the induction of endoplasmic reticulum (ER) stress, co-operate to enhance astrocyte activation & apoptosis, hallmark features of HAND. This will be tested via three specific aims: a) To examine the role of ER stress in HIV Tat &/or cocaine mediated upregulation of astrogliosis (upergulation of GFAP) in both rat and human primary astrocytes, b) To investigate the signaling pathways involved in HIV Tat &/or cocaine mediated enhancement of astrogliosis and c) To test in vivo the therapeutic potential of inhibition of ER response as an intervention strategy for ameliorating Tat & or cocaine-mediated astrogliosis in rodent models of HAND.